Melphalan is the L enantiomer of 4-[bis(2-chloroethyl)amino]phenylalanine of formula I:

This compound is also known with the name of L-PAM, L-sarcolysine, NCS-8806, CB3025.
Melphalan is commercially known with the name of Alkeran™ in the form of tablets or injectable preparations.
Melphalan is a compound known for its antitumor properties; its D enantiomer and the racemic mixture also have antitumor activity but of small degree.
Melphalan is particularly used in the treatment of multiple myeloma and ovarian cancer.
Melphalan is synthesized according to the processes disclosed in U.S. Pat. Nos. 3,032,584 and 3,032,585 starting from DL-phenylalanine with a process comprising the following steps:                1. nitration in the presence of nitric acid and sulfuric acid;        2. protection of the glycine amino group as acetyl, formyl or phthtaloyl derivative followed by esterification of the carboxy group;        3. reduction of the nitro group to amine by hydrogenation;        4. hydroxyethylation reaction of the amine on the aromatic ring in the presence of ethylene oxide;        5. chlorination in the presence of POCl3 or SOCl2;         6. resolution of the racemic mixture and isolation of L-enantiomer;        7. deprotection of the glycine amino group and hydrolysis of the ester.        
RO 57195 discloses the isolation of melphalan hydrochloride by adding diethyl ether to the aqueous solution containing it, followed by the addition of Na2CO3 or NaOAc to bring the pH to 0.5 and subsequently to 1.5-2. The purification is carried out by dissolving in HCl melphalan hydrochloride obtained by the treatment at pH=2.
GB 750,155 discloses the synthesis of melphalan starting from 4-[bis(hydroxyethyl)amino]phenylalanine ethyl ester by reaction with POCl3or SOCl2 in the optional presence of an inert solvent to give the chlorine derivative followed by a reaction with HCl to remove the protective groups.
GB 783,292 discloses the synthesis of melphalan starting from its non optically active precursors by resolution of some intermediates of the synthesis as brucine salts. It is particularly disclosed the separation of brucine diastereomeric salts of N-acetyl-4-nitro-DL-phenylalanine. The L-isomer, suitably purified from the residues of brucine, is hydrolysed to give 4-nitro-phenylalanine, followed by the esterification with phthalic anhydride, the reduction of the nitro group, the reaction of the resultant amine with ethylene oxide, the reaction with POCl3 or SOCl2 to obtain the chlorine derivative, the removal of the phthaloyl protective group and of the ethyl ester to give 4-bis-(2-chloroethyl)-aminophenylalanine.
CN 101100440 discloses a process for the preparation of melphalan hydrochloride comprising:                the esterification of the carboxyl group of 4-nitrophenylalanine in EtOH        the protection of the amine in the presence of TEA to give the N-Boc derivative        the hydrogenation of the nitro group        the hydroxyethylation reaction in the presence of ethylene oxide        the chlorination reaction of the OH groups        the deprotection reaction of the amino group        the hydrolysis reaction with 2M-6M hydrochloric acid to remove the protective groups and to obtain the final compound.        
EP 0 317 281 discloses the preparation of melphalan hydrochloride by reaction of the N-phthaloyl derivative with ethylene oxide, followed by chlorination, hydrolysis and subsequent formation of melphalan hydrochloride.
WO 2009/117164 discloses a process for the synthesis of melphalan characterized by the fact that the hydroxyethylation reaction of the aromatic NH2 group is carried out without the need to protect the glycine NH2 group.
US 2012/0190887 discloses a process for the preparation of pharmaceutical grade melphalan hydrochloride comprising a purification step by dissolving in hydrochloric acid, adding active charcoal, adding alkali hydroxide, filtering and washing with deionized water, slurrying with isopropyl ether.
US 2012/0116117 discloses a process for the preparation of melphalan hydrochloride with HPLC purity >99% i.e. conforming to drug regulation specifications.
In the processes described in the state of the art, melphalan is isolated and purified through some steps that provide a precipitation of melphalan in water saturated with sodium acetate at pH=7 followed by one or more crystallizations from methanol or a precipitation in the presence of diethylamine at pH=7, followed by washing with methanol.
Most of the purification methods disclosed in the state of the art need to bring the pH to neutrality after the treatment with aqueous hydrochloric acid necessary for the removal of the amine and carboxy protective groups, to allow the precipitation of melphalan.
These purification methods yield melphalan with a purity from 96% to 99%.
The precipitation of melphalan at pH=7, according to the processes known in the state of the art, leads to the formation of a highly unstable solid which is particularly hard to filter because of its sponginess. The instability of said spongy solid leads to the formation of an impurity, called “dimer” (impurity G—4-[[2-[[4-[bis(2-chloroethyl) amino]-L-phenylalanine]oxy]ethyl]-(2-chloroethyl)amino]-L-phenylalanine) according to European Pharmacopeia 2012, pages 4658-4659). The limit values of such impurity, reported into the European Pharmacopeia, are high (limit NMT 1.0%) just because of the difficult in the removal of the “dimer” in the process for the production of melphalan.